AIDSWEEKLY Plus, 16 September 1996
Daniel J. DeNoon, Senior Editor

But exactly how the vaccine worked is unknown: the protected animals had very low levels of antibodies capable of neutralizing HIV, and had no detectable anti-HIV antibodies in their vaginal mucosa at the time of challenge.

"Female chimpanzees can be protected from vaginal challenge by repeated mucosal and systemic immunization with a live recombinant canarypox virus," said Marc Girard of the Pasteur Institute, Paris, France.

"The results suggest that neutralizing antibodies may be less important for protection from mucosal infection than from intravenous challenge."

The five adult chimpanzees received multiple immunizations with a Virogenetics HIV vaccine expressing the HIV-1[LAI] gp120 envelope/transmembrane, gag, and protease genes.

Two animals were immunized simultaneously via the intramuscular, cervico-vaginal, and rectal routes; two animals were immunized via the intramuscular, nasal, and oral routes; and one animal received intramuscular immunization only. One HIV- and vaccine-naive animal served as a control.

Immunizations were administered at months 0, 2, 6, 13, and 17.

"The canarypox, as we already know, is not a very good immunogen to induce humoral immunity because after two immunizations only one of the animals started responding; the other four animals responded only transiently after a third immunization," Girard said. "It was only after four immunizations that we really got an immune response and we could detect neutralizing antibodies."

Nevertheless, these antibody levels were low.

"Oral/nasal immunized animals had significantly lower [anti-gp120/160] titers than the other ones," Girard said. "Only two of the animals showed antibodies that could prevent syncytium formation in an in vitro assay. ... We could not detect anti-HIV IgG in vaginal washes. ... Very little gp120/160 antibody was induced by inoculation."

One month after the last boost the animals were challenged with 2500 culture-infectious doses of HIV-1[LAI]. One of the vaccinated animals, in estrus at the time, was not challenged.

Only the control animal became infected, despite the fact that no anamnestic antibody response could be detected in any of the protected animals.

After another booster immunization all five animals and another control animal were again challenged with infectious HIV. This time two of the vaccinated animals became infected.

"Three of the five were protected, however, this experiment is complicated because the control animal did not become infected," Girard noted.

Again, antibody titers did not predict which animals would become infected. The two vaccinated animals that became infected had the highest and the lowest titers of HIV- neutralizing antibodies.

"I think this is a big difference from what we have observed previously in the intravenous challenge experiment where there was a good correlation between neutralizing antibodies - mostly V3-targeted neutralizing antibodies - and protection from HIV-1[IIIB] infection," Girard said.

He was asked how the animals were protected.

"It is unfortunate that at this time it is more a matter of guessing than anything else," Girard replied. "We have not been able to detect CTLs [cytotoxic lymphocytes] either at the first or the second challenge. Neutralizing antibodies, as I showed you, do not correlate with protection. Of course one can think of chemokines or other cellular immune responses but we have not monitored those."

Findings from small clinical trials completed in 1996 provide tantalizing hints of efficacy for a vaccination strategy including the canarypox vaccine.

This so-called prime/boost approach employs two candidate HIV vaccines: priming with ALVAC/HIV followed by boosting with a recombinant HIV gp120 subunit vaccine (rgp120MN in MF59 adjuvant, Chiron/Biocine).

Earlier in 1996, NIAID Director Anthony Fauci predicted that if Phase II trials are successful - defined as confirmation of cytotoxic lymphocyte (CTL) and antibody induction, safety, and either protection of primates in concurrent challenge studies or evidence of clinical efficacy - Phase III trials could begin as early as the third quarter of 1998.

So far, early studies have been highly successful. Human trials have proven that the approach is safe and can induce both CTL and neutralizing antibodies.

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